Certain thiazolyl- and pyridinylaminoketones



United States Patent 3,514,465 CERTAIN THIAZOLYL- AND PYRIDINYL-AMINOKETONES Klaus Posselt, Bergen Enkheim, and Kurt Thiele, Frankfurtam Main, Germany, assignors to Deutsche Goldund Silber-Scheideanstaltvormals Roessler, Frankfurt am Main, Germany No Drawing. Filed Dec. 26,1967, Ser. No. 693,138 Claims priority, application Germany, Dec. 30,1966, D 51,910, D 51,911 Int. Cl. C07d 31/42, 91/32 US. Cl. 260296 8Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula their saltsand quaternary ammonium compounds, as well as their optically activeisomers or diastereomers wherein R to R represent hydrogen, halogen,lower alkyl, aralkyl, phenyl, hydroxyl, lower alkoxy, nitro or lowercarboalkoxy, R and R are hydrogen or methyl, R and R are hydrogen,halogen or lower alkoxy, X is a heterocyclic ring system, monoorcondensed bicyclic, with 1-4 hereto atoms, in which the individual ringshave 5 to 6 members and can also contain 1 or more carbonyl groups, Y is-CO or CH(OH)-. These compounds have pharmacological activity in thatthey increase the coronary blood flow by simultaneously causing dilationof the coronaries and an increase in contraction strength.

DETAILED DESCRIPTION OF THE INVENTION INCLUDING PREFERRED EMBODIMENTSThe following heterocyclic ring systems, for example, come intoconsideration for the compounds according to the invention: furane,thiophene, pyrrole, pyrazole, thiazole, pyridine, pyrimidine, triazine,pyrazolone, benzofurane, benzothiophene, indole, quinoline,isoquinoline, benzodioxol, benzodioxane, decahydroisoquinoline,benzothiazole and benzimidazole.

The compounds according to the invention of the above Formula I can beproduced in a known manner by (a) Reacting a compound of the formula Il-O 0-0 H; R I t R5 II with a compound of the formula R7 HNCH(OH) 1'2 R8III in the presence of formaldehyde or a formaldehyde source and asolvent.

(b) Reacting a compound of the formula R R1 V 0 OC=G H2 l s i 1'15 IV orthe corresponding Mannich base of the formula wherein R and R are loweralkyl with a compound of Formula III or 3,514,465 Patented May 26, 1970(c) Reacting a compound of the formula with a compound of the formula inwhich W and V are dilferent and are either halogen or NH in the presenceof a basic substance and, if desired, in the event Y is'CO, reducingsuch group to a CH(OH) group and, if desired, converting the basesproduced into their pharmacologically acceptable acid addition salts orquaternary ammonium salts.

The process according to method (a) is carried out in the usual mannerat a temperature between 20 and 150 C. Alcohols, dioxane, glacial aceticacid and the like come into consideration as solvents.

The process according to method (b) in general when using an unsaturatedketone of Formula IV can be carried out at temperatures between 20 andC. in an inert solvent, such as, ether, acetone, dioxane or chloroform,whereas when the corresponding Mannich base is used, which during thereaction is transformed into an intermediate of Formula IV, the reactiontemperature used is normally higher, preferably, between 80 and C., andsolvents such as water, alcohol/Water, or a two phase system such asbenzene/ water toluene/ water come into consideration.

The process according to method (c) is usually carried out at elevatedtemperatures in a solvent such as alcohols, ether, dimethyl formamideand the like.

The compounds produced which contain optically active carbon atoms andwhich as a rule are produced as racemates can be resolved into theiroptically active isomers in the usual manner, for example, with the aidof an optically active acid. It, however, is also possible to employoptically active compounds or diastereomers as the starting materialswhereby the end product in the corresponding pure optically active formor disastereomeric configuration is obtained.

The free bases can be converted into their salts with the usualpharmacologically acceptable acids such as HCl, HBr, H 80 acetic acid,citric acid, succinic acid, maleic acid, fumaric acid, lactic acid,p-toulene sulfonic acid and the like. Those compounds containing basictertiary nitrogen atoms can be converted to their quaternary salts withthe usual pharmacologically acceptable quaternizing agents such as thelower alkyl halides. The free bases can be removed from the salts, forexample, by treatment with aqueous NaOH and other salts can be preparedfrom such free bases.

As already indicated, the com-pounds according to the invention have apharmacological activity in that they increase the coronary blood flowby causing dilation of the coronaries, as well as an increase incontraction strength of the heart.

When tested on the isolated guinea pig heart according to Langendorff(Pfliigers Arch. 61, 219, 1889) it was found that the compoundsaccording to the invention were active in doses between 1050(),ug./heart ig. ='y=microgram) in dilating the coronaries whilesimultaneously increasing the contraction strength.

The indications for the compounds according to the invention are:

Coronary insufficiency Angina pectoris Myocardial infarct Myocardialinsufiiciency Circulatory disturbances of various geneses Disturbancesof the peripheral and cerebral blood flow Migraines Arteriosclerosis Thenovel compounds can be used, if desired, also in combination with othermedicaments in the form of pharmaceutical compositions suited forenteral, parenteral, oral or per lingual application.

The acute toxicity of the compounds according to the invention whentested on mice by the method of Miller and Tainter (Proc. Soc. exper.Biol. a Med. 57, 261, 1944) expressed as the LD 50 is between 100 mg./kg. and 5000 mg./kg. oral.

The individual doses for human beings, depending on form ofadministration are between 0.5 and 100 mg., once or more times a day.

The following examples will serve to illustrate the compounds accordingto the invention. For sake of simplicity the symbol Z is used in thestructural formulae and nomenclature of a number of the examples torepresent, respectively and 2- [3-phenyl-3-hydroxy-propyl-(2)-amino]-ethyl Example 1 1-{2-[3 phenyl 3 hydroxypropyl-(2)-amino-ethyl}- thienyl (2) ketone, that is, 1-{Z}-thienyl (2)-ketone Method (a).l2.6 g. (0.1 mol) of 2-acetyl thiophene 18.7 g. (0.1mol) of 1-norephedrine-HC1 and 4 g. (0.13 mol) of paraformaldehyde weredissolved in ml. of isopropanol and after addition of 0.2 mol ofconcentrated HCl boiled under reflux for 2 hours. Thereafter 100 ml. ofacetone were added to the still warm solution. The hydrochloride whichcrystallized out upon cooling was purified by recrystallization fromethanol. Its melting point was 191-192" C. and the yield 17 g.

Method (b).1.5 g. (0.01 mol) of l-norephedrine were dissolved in 50 ml.of ether and 2.7 g. (0.02 mol) of thienyl vinyl ketone dissolved in 10ml. of ether added thereto. After /2 hour 2 g. of the base separated outwhich after recrystallization from ethanol had a melting point of118-120 C. The hydrochloride produced therefrom had a melting point of19l192 C.

Method (c).--5.2 g. (0.03 mol) of Z-[B-chloropropionyl]-thiophene weredissolved in dimethyl formamide and united with a solution of 4.5 g.(0.03 mol) of 1- norephedrine and 4 g. (0.03 mol) of triethylarnine inml. of dimethyl formamide. After 1 hour the triethylamine HCl which wasformed was filtered off and the filtrate acidified with isopropanolicHCl. Subsequently, the HCl salt was precipitated from the solution byaddition of ether and recrystallized from ethanol. Its melting point was19l-l92 C. and the yield was 7 g.

Example 2 1-{Z}-phenyl-(2)-ketone 11 g. (0.1 mol) of Z-acetyl-furan,18.7 g. (0.1 mol) of 1-norephedrine-HC1 and 4 g. (0.13 mol) ofparaformaldehyde were heated for 2 hours under reflux in 20 4 ml. ofisopropanol with the addition of 5 drops of ethanolic HCl. The HCl saltwhich had precipitated out was stirred up with 50 ml. of acetone andfiltered oil. It was purified by recrystallization from ethanol. Itsmelting point was l86-187 C. and the yield was 10.5 g.

Example 3 1-{Z}- [4-methyl-thiazolyl- (2) ]-ketone 7 g. (0.05 mol) of4-methyl-2-acetyl-thiazole, 9.4 g. (0.05 mol) of l-norephedrine-HCl, 2g. (0.067 mol) of paraformaldehyde and 5 drops of isopropanolic HCl in20 ml. of isopropanol were reacted and processed as in Example 2. TheHCl salt was recrystallized from methanol. Its melting point was 197199C. and the yield 7 g.

Example 4 1{Z}-antipyryl-(4)-ketone 11.5 g. of 4-acetyl-antipyrin (0.05mol), 9.5 g. of 1- norephedrine-HCI (0.05 mol) and 2 g. ofparaformaldehyde (0.067 mol) were introduced into 20 ml. of isopropanoland 5 drops of isopropanolic HCl added thereto and the mixture boiledfor a total of 5 hours during which after 3 hours an additional 1 g. ofparaformaldehyde was added. Thereafter the solvent was distilled off andthe residue treated with aqueous soda. The oily Mannich base producedwas crystallized with the aid of ether. It formed the dihydrochloridewith 2 mol of HCl which was recrystallized from ethanol. Its meltingpoint was 206-208 C. and the yield was 9 g.

Example 5 1-{Z}-pyridyl- (3 )-ketone 40 g. (0.33 mol) ofS-acetyl-pyridine, 18.7 g. (0.1 mol) of l-norephedrine-HCl and 3 g. (0.1mol) of paraformaldehyde were boiled under reflux in 15 ml. ofisopropanol for a total of 3 hours. An additional 1 g. ofparaformaldehyde was added after 1 hour. Thereafter the reaction mixturewas diluted with acetone and the precipitated I-ICl salt wasrecrystallized from methanol/ ethanol (1 :2). Its melting point was187-189 C. and the yield 7 g.

Example 6 1-{Z}- [2,4-dimethyl-thiazolyl-(5 ]-ketone 25 g. (0.16 mol) of2,4-dimethyl-5-acetyl-thiazole, 30 g. (0.16 mol) of l-norephedrine-HCIand 5 g. (0.16 mol) of paraformaldehyde were introduced into 50 ml. ofisopropanol and 15 drops of isopropanolic HCl added thereto. The mixturewas boiled on a water bath for a total of 1 hour. An additional 1.5 g.of paraformaldehyde was added after /2 hour. The reaction solution 'wasdiluted with 100 ml. of acetone while still warm. The HCl salt whichprecipitated out was recrystallized from ethanol. Its melting point was208210 C. and the yield 6.6 g.

from methanol/ethanol (1:1). Its melting point was 209 210 C. and theyield 4.5 g.

Example 8 1-{Z}-cumaronyl-ketone CO-Z 40 g. (0.25 mol) of 2-acetylcumarone, 46.5 g. (0.25 mol) of l-norephedrine-HCl and 7.5 g. (0.25 mol)of paraformaldehyde were dissolved in 200 ml. of isoamyl alcohol andafter addition of 10 drops of ethanolic-HCl boiled under reflux for /2hour. Then an additional 2.5 g. (0.083 mol) of paraformaldehyde wereadded and the mixture refluxed for a further hour. The solution wasdiluted with 100 ml. of acetone while still warm. Upon cooling the HClsalt crystallized out. It was recrystallized from ethanol. Its meltingpoint was 199-200 C. and the yield 31.5 g.

Example 91-3-{3-[3-phenyl-3-hydroxy-propyl-(2)-amino1-propionyl}-thionaphtheneCOZ 17.6 g. (0.1 mol) 3-acetyl-thionaphthene, 18.7 g. (0.1 mol) ofl-norephedrine-HCI and 4.5 g. (0.15 mol) of paraformaldehyde were boiledunder reflux for 2 hours in 50 ml. of isopropanol. The solution was thendiluted with 100 ml. of acetone while still warm. Upon cooling the HClsalt precipitated out. It was recrystallized from methanol. Its meltingpoint was 200-221 C. and the yield 18.5 g.

Example 10 1-3-{3- [3-phenyl-3 -hydroxy-propyl- (2) -amino propionyl}-l-methyl-indole [COZ on. i

25 g. (0.13 mol) of 1-methyl-3-acetyl-indole, 24.3 g. (0.13 mol) ofl-norephedrine-HCI and 5 g. (0.17 mol) of paraformaldehyde weredissolved in 100 ml. of isopropanol and boiled under reflux for a totalof 6 hours. After the second and fourth hours an additional 2.5 g. ofparaformaldehyde were added. Thereafter the solvent was distilled offand the residue dissolved in warm acetone. The HCl salt whichcrystallized out on cooling was recrystallized from ethanol. Its meltingpoint was 194-195 C. and the yield 22 g.

6 Example 11 1-5-{3- [3-phenyl-3-hydroxy-propyl- (2) -amino]propionyl}-benzodioxol- 1,3)

8 g. (0.048 mol) of 5-acetyl-benzodioxol-(1,3), 9.1 g. (0.048 mol) ofl-norephedrine-HCl and 2.9 g. (0.097 mol) of paraformaldehyde wereboiled on a water bath for 2 hours in 30 ml. of isopropanol afteraddition of 5 drops of isopropanolic HCl. After addition of 100 ml. ofacetone to the warm reaction solution, the HCl salt precipitated out. Itwas recrystallized from ethanol. Its melting point was 195-197 C. andthe yield 9 g.

Example 12 1-4-{3-[3-phenyl-3-hydroxy-propyl-(2) amino] pr0pi0nyl}-1,3-dimethyl and -1,5-dimethyl pyrazole (mixture) 26 g. (0.19 mol)of the isomeric mixture of 1,3- and 1,5-dimethyl-4-acetyl-pyrazoleformed during the synthesis, 37.4 g. (0.2 mol) of 1-norephedrine-HCl and9 g. (0.3 mol) of paraformaldehyde were boiled under reflux under anatmosphere of nitrogen in 150 m1. of isopropanol for 3 hours. Uponcooling the HCl salt crystallized. It was recrystallized fromisopropanol and then twice from ethanol. Its melting point was 196 C.and the yield 11 g.

Example 13 1-{Z}-quinoyl- (3 -ketone 10 g. (0.058 mol) of 3-acetylquinoline, 11.2 g. (0.058 mol) of 1-norephedrine-HCl and 1.6 g. (0.058mol) of paraformaldehyde were boiled under reflux on a water bath in ml.of isopropanol for 2.5 hours. An additional 0.8 g. (0.026 mol) ofparaformaldehyde was added after 1 hours boiling. Upon addition of 150ml. of acetone the HCl salt precipitated out. It was recrystallized frommethanol. Its melting point was 205-206 C. and the yield 5 g.

Example 14 l-{Z}-isoquinolyl- (4) -ketone 5 g. (0.024 mol) of 4-acetylisoquinoline-HCI, 4.6 g. (0.024 mol) of l-norephedrine-HCl and 0.7 g.(0.024 mol) of paraformaldehyde were boiled on a Water bath. for.2.5hours in 50 ml. of a 1:1 mixture of ethanol-isopropanol and anadditional 0.4 g. (0.012 mol) of paraformaldehyde was added after 1hours boiling. Upon cooling, the dihydrochloride salt precipitated out.It was recrystallized from ethanol. Its melting point was 208 C. and theyield 3 g.

7 Example 15 1-{Z}-[ 1,2,4-trirnethyl-S-carbethoxypyrrolyl- 3 ketone 18g. (0.081 mol) of 1,2,4-trimethyl-3-acetyl-5-carbethoxypyrrole, 15.2 g.(0.081 mol) of l-norephedrine-HCl and 2.4 g. (0.081 mol) ofparaformaldehyde were boiled on a water !bath for 1.5 hours in 50 ml. ofisopropanol. An additional 1.2 g. of paraformaldehyde were added after/2 hours boiling. Upon addition of 100 ml. of acetone the HCl saltprecipitated out. It was recrystallized -from ethanol. Its melting pointwas 178- 180 C. and the yield 10 g.

Example 16 1-6{3- 3-phenyl-3-hydroxy-propyl- (2) -amino]propionyl}-benzodioxane-( 1,4)

out was recrystallized from ethanol. Its melting point was 201 C. andthe yield 7.5 g.

Example 17 1-2-{3-[3-phenyl-3-hydroxy-propyl-(2)-amino]-propionyl}-henzodioxane-( 1,4)

(I Tao-Z 11 g. (0.061 mol) of 2-acetyl-1,4-benzodioxane, 11.6 g. (0.062mol) of l-norephedrine-HCl and 1.85 g. (0.062 mol) of paraformaldehydewere reacted in 30 ml. of isopropanol and processed as in Example 16.The melting point of the HCl salt was 178 C. and the yield 8 g.

Example 18 1- {Z}- [2-benzyl-10-hydroxy-decahydroisoquinolyl- (4)-ketone OH CO-Z IMHPQ 11 g. (0.0339 mol) of2-benzyl-4-acetyl-IO-hydroxydecahydroisoquinoline-HCl, 6.5 g. (0.035mol) of l-norephedrine-HCl and 1.4 g. (0.047 mol) of paraformaldehydewere boiled on a water bath for 2 hours in 35 n11. of isopropanol. Anadditional 1.4 g. of paraformaldehyde were added after 1 hours boiling.The solvent was then distilled off and acetone and ethyl acetate addedto the residue. The dihydrochloride produced was recrystallized fromethanol. Its melting point was 182-183 C. and the yield 7 g.

8 Example 19 1-{Z}- [S-nitro-furyl- (2) -ketone 11.6 g. (0.075 mol) ofZ-acetyl-S-nitro-furane, 14 g. (0.075 mol) of l-norephedrine-HCI and 3g. (0.1 mol) of paraformaldehyde in 50 m1. of isopropanol were heated ona water bath for 3 hours. The HCl salt which precipitated out uponcooling was recrystallized from ethanol. Its melting point was 210 C.and the yield 3 g.

Example 20 1-4-{3- 3-phenyl-3-hydroXy-propyl- 2) -amino]propionyl}-1,3,5-trimethyl pyrazole 27 g. (0.178 mol) of1,3,5-trimethyl-4-acetyl-pyrazole, 33 g. (0.177 mol) ofl-norephedrine'Hcl and 10.8 g. (0.36 mol) of paraformaldehyde in 150 ml.of isopropanel were heated for 2 hours on a water bath. Thereafter thesolvent was distilled off and ml. acetone were added to the residue. TheHCl salt which precipitated' was recrystallized from isopropanol. Itsmelting point was 191 C. and the yield was 14.5 g.

Example 21 1-4-{ 3- 3-phenyl-3 -hydroxy-propyl- 2) -amino]-propi0nyl}-1-benzyl-3 ,5 -dimethyl-pyrazole O HQW E C O-Z i N CH3 CHPQ13.5 g. (0.0624 mol) of 3,S-dimethyl-1-benzyl-4-acetylpyrazole, 11.1 g.(0.0593 mol) of l-norephredrine-HCI and 3. 6 g. (0.12 mol) ofparaformaldehyde were heated on a water bath in 200 ml. of isopropanolfor 2 hours. The HCl salt precipitated out from the reaction solutionafter addition of 100 ml. of acetone and it was recrystallized fromethanol. Its melting point was 200 C. and the yield 11 g.

Example 22 d,1-{2- [3- 3-fluoro-4-methoxy-phenyl) -3-hydroxy-propyl- (2-amino] -ethy1}-thienyl- 2) -ketone L lco-om-cm-rrn-dn-omom-Qocu.

28 g. (0.119 mol) of d,l-3-(3-fluoro-4-methoxy-phenyl)-3-hydroxy-propyl- (2) amine-HCl, 15 g. (0.119 mol) of Z-acetyl-thiopheneand 7.2 g. (0.24 mol) of paraformaldehyde were reacted in 200 ml. ofisopropanol and processed as in Example 21. The HCl salt wasrecrystallized from ethanol. Its melting point was 208 C. and the yieldwas 10 g.

Example 23 1-{- [3-phenyl-3-hydroxy-propyl- (2 -amino] propyl- (2)}-thienyl- 2 -ketone 43 g. (0.307 mol) of 2-propionyl-thiophene, 57.7 g.(0.308 mol) of l-norephedrinerHCl and 18.4 g. (0.614 mol) ofparaformaldehyde were heated on a water bath 9 in 50 ml. of isopropanolfor 1 hour. 100 ml. of acetone were added to the reaction solution andthe HCl salt which precipitated out recrystallized from ethanol. Itsmelting point was 208 C. and the yield was 16.5 g.

Example 24 1-{Z}-5-chloro-thienyl-(2)-ketone 30 g. (0.187 mol) of2-acetyl-S-chloro-thiophene, 35 g. (0.187 mol) of l-norephedrine-I-ICland 5.6 g. (0.187 mol) of paraformaldehyde were heated in 50 ml. ofisopropanol and processed as in Example 21. The HCl salt wasrecrystallised from ethanol. Its melting point was 198 C. and the yieldwas 16 g.

Example 25 d, l-{2- [2- (2-chloro-phenyl 2-hydroxy-ethylamino] ethyl}thienyl- (2 ketone 12.6 g. (0.1 mol) of 2-acetyl-thiophene, 20.8 g. (0.1mol) of d,1-2-( 2 chloro phenyl) 2 hydroxy ethylamine-HCI and 4.5 g.(0.15 mol) of paraformaldehyde were heated on a water bath for 2 hoursin 100 ml. of isopropanol. Thereafter the solvent was distilled off andthe residue caused to crystallize by addition of ethyl acetate. The HClsalt produced was recrystallized from ethanol. Its melting point was158-160 C. and the yield was 4 g.

Example 26 [3-phenyl-3 hydroxy-propyl- (2) ]-{3- [4-phenyl-thiazolyl- (2]-3-hydroxypropyl-( 1 }-a1nine 6 g. (0.015 mol) of1-{Z}-[4-phenyl-thiazolyl-(2)]- ketone-HCl were suspended in 60 ml. ofmethanol and reduced by the addition of 0.6 g. (0.016 mol) of sodiumborohydride. After 1 hour the solvent was distilled OE and the residuedissolved in acetone. Fumaric acid was added to such solution toprecipitate out the fumar-ate salt. The base was again set free from thefumarate with aqueous NaOH. The resulting oily base was taken up inether and converted to the HCl salt with isopropanolic HCl and such saltrecrystallized from ethanol. Its melting point was 178-l81 C. and theyield was 2.5 g.

Example 27 [3phenyl-3hydroxy-propyl- (2) ]-{3- [thienyl- (2)3-hydroxy-propyl-( l }-amine 63 g. (0.2 mol) of1-{Z}-thienyl-(2)-ketone-HC1 and 300 g. of aluminum isopropylate wereheated to 130 C. for 2 hours in 2 liters of isopropanol and the acetoneproduced during the reduction distilled ofi over a column. After 7 hoursthe cooled solution was decomposed by addition of 100 g. of citric acidin 200 ml. of water and then rendered strongly alkaline with aqueousNaOH. The organic phase was dried over calcium oxide and the solventdistilled off under vacuum. The amino alcohol product melted at 123125C. after it was recrystallized from 50% ethanol. Upon addition of anequimolar quantity of HCl a HCl salt was obtained which had a meltingpoint of 152-155 C. The yield was 13 g.

1 0 Example 28 -[3-phenyl-3hydroxy-propyl- (2) 3- [cumaronyl- (2)-3-hydroxy-propyl-( 1 }-amine 18 g. (0.05 mol) ofl-{Z}-cumaronyl-ketone-HCl were suspended in ml. of ethanol and reducedat room temperature with 2 g. of sodium borohydride dissolved in 50 ml.of ethanol. After 1 hour, 50 ml. of concentrated HCl were added and theNaCl produced filtered 01f. The solvent was then distilled olf undervacuum and the residue recrystallized from isopropanol/ethyl acetate(1:1). The HCl salt produced melted at 210-215 C. with decomposition.The yield was 11 g.

Example 29 [3-phenyl-3-hydroxy-propyl- (2) [3-thionaphthenyl- (3)]-3-hydroxy-propyl- 1 }-amine 19 g. (0.05 mol) 1-3-[phenyl 3hydroxy-propyl-(2)- amino]propionyl}thionaphtheneHCl were suspended in100 ml. of ethanol and reduced with 2 g. of sodium borohydride in 50 ml.of ethanol at room temperature. After 1 hour the reaction mixture wasfiltered and the solvent distilled off and the residue dissolved inether. The HCl salt was precipitated from the ether solution by additionof ethanolic HCl and recrystallized from isopropanol. Its melting pointwas 167-170 C. and the yield was 12 gl We claim:

1. A compound selected from the group of compounds of the formula 1 h ln their pharmacologically acceptable salts and their pharmacologicallyacceptable quaternary ammonium salts, wherein Z is HC=CH or S, n is 0 to4 when Z is and n is 0 to 2 when Z is S, R is selected from the groupconsisting of halogen, lower alkyl, phenyl, hydroxyl, nitro and lowercarboalkoxy, R and R are selected from the group consisting of hydrogenand methyl, R, and R are selected from the group consisting of hydrogen,halogen and lower alkoxy, and Y is selected from the group consisting ofCO- and -CH(OH).

2. A compound according to claim 1 wherein Z is S.

3. A compound according to claim 2 wherein when n is 1, R is lower alkyland when n is 2, at least one R is lower alkyl and the other R is eitherlower alkyl or hydroxyl.

4. A compound according to claim 3 which is 1-(2-[3- phenyl 3hydroxypropyl-(2)-amino]-ethyl)-[4-methylthiazoyl- 2) ketone.

5. A compound according to claim 3 which is 1-(2- [3 phenyl 3hydroxypropyl-(2)-amino]ethyl) -2,4-dimethylthiazoyl- (5 ]-ketone.

6. A compound according to claim 3 which is l-(2-[3- phenyl 3hydroxypropyl-(Z)aminojlethyl- [4-methyl-2- hydroxythiazolyl- 5 -ketone.

11 12 7. A compound according to claim 1 wherein Z is ALEX MAZEL,Primary Examiner -HO==OH.

8. A compound according to claim 7 wherein n is 0. GALLAGHER AsslstantExammer References Cited 260288 295 302 3 1 326 3 32615 3305 5 a a a 3 9I UNITED STATES PATENTS 332.3, 340.3, 340.5, 346.2, 347.7, 999

2,556,636 6/1951 Sperber et a1 260302

